Method of preparing deoxyribofuranose compounds

ABSTRACT

The invention relates to methods for making deoxyribofuranose compounds such as compound (2) which are useful intermediates in the preparation of pharmaceutical compounds such as 5-amino-3-(2′-O-acetyl-3′-deoxy-β-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. applicationSer. No. 13/129,730 filed Aug. 9, 2011, which is a national stageapplication of International Application Number PCT/US09/64605 filedNov. 16, 2009, which claims the benefit of U.S. Provisional ApplicationNo. 61/115,134, filed Nov. 17, 2008, the entire contents of which areincorporated herein.

FIELD OF THE INVENTION

The invention relates to methods for making deoxyribofuranose compoundswhich are useful intermediates in the preparation of pharmaceuticalcompounds such as5-amino-3-(2′-O-acetyl-3′-deoxy-β-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-oneand the like.

BACKGROUND OF THE INVENTION

Nucleoside analogs are an important class of compounds that are usefulin the treatment of disease. For example, nucleoside analogs have beenused in the treatment of cancers and viral infections. After entry intoa cell, nucleoside analogs are frequently phosphorylated by nucleosidesalvage pathways in which the analogs are phosphorylated to thecorresponding mono-, di-, and triphosphates. Among other intracellulardestinations, triphosphorylated nucleoside analogs often serve assubstrates for DNA or RNA polymerases and become incorporated into DNAand/or RNA. Where triphosphorylated nucleoside analogs are strongpolymerase inhibitors, they may induce premature termination of anascent nucleic acid molecule. Where triphosphorylated nucleosideanalogs are incorporated into nucleic acid replicates or transcripts,gene expression or disruption of function may result.

Some nucleoside analogs may be efficacious because of their ability toinhibit adenosine kinase. Adenosine kinase catalyzes the phosphorylationof adenosine to adenosine 5′-monophosphate (AMP). Inhibition ofadenosine kinase may effectively increase the extracellular level ofadenosine in humans and thereby serve as a treatment of ischemicconditions such as stroke, inflammation, arthritis, seizures, andepilepsy.

The last few decades have seen significant efforts expended in exploringtherapeutic uses of nucleoside analogs. For example, certainpyrimido[4,5-d]pyrimidine nucleosides are disclosed in U.S. Pat. No.5,041,542 to Robins et al. as being effective in treatment against L1210in BDF1 mice. Additionally,3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidines demonstrating significantimmunoactivity, including murine spleen cell proliferation and in vivoactivity against Semliki Forest virus, are disclosed in U.S. Pat. Nos.5,041,426 and 4,880,784 to Robins et al. A number of publications havealso described non-glycosyl derivatives of the thiazolo[4,5-d]pyrimidinemoiety. See, e.g., U.S. Pat. Nos. 5,994,321 and 5,446,045; Revankar etal., J. HET. CHEM., 30, 1341-49 (1993); and Lewis et al., J. HET. CHEM.,32, 547-56 (1995).

3,5-Disubstituted-3H-thiazolo[4,5-d]pyrimidin-2-one compounds have beenshown to have immunomodulatory activity. The preparation and usefulnessof this class of compounds is discussed in U.S. Application PublicationNo. US2006/0160830 (U.S. application Ser. No. 11/304,691), and U.S.application Ser. No. 11/873,202, both of which are incorporated hereinby reference in their entireties.

SUMMARY OF THE INVENTION

The invention is directed to a method for preparing compound (2)

comprising(i) reacting compound (4) with an alkyl ketene acetal and catalytic acid

to form a cyclic compound of Formula (5)

wherein R¹ is a lower alkyl,(ii) hydrolysing the compound of Formula (5) with water and a catalyticor stoichiometric amount of acid to form a mixture of monoacylsubstituted compounds (6) and (7),

(iii) equilibrating the mixture of monoacyl substituted compounds (6)and (7) to cause an excess of compound (6),(iv) oxidizing the mixture of compound 6 and compound 7 to form themixture of ketone of compound (8) and hydrated ketone of compound (9)

(v) reducing the mixture of ketone of compound (8) and hydrated ketoneof compound (9) to form compound (10) or reducing compound (8) andcompound (9) separately to form compound (10)

(vi) sulfonating compound (10) with a sulfonating agent in the presenceof a base to form compound of Formula (11)

wherein R² is an optionally substituted alkyl or aryl,(vii) displacing the sulfonate ester compound of Formula (11) with ahalogen atom to form a halogen compound of Formula (12)

wherein X is halo,(viii) reducing the halogen of the Formula (12) compound to a hydrogenatom to form compound (13)

and(ix) treating compound (13) with an acid catalyst and acylating agent toform compound (2).

In one embodiment of the invention, R¹ is —CH₃ or —CH₂CH₃.

In one embodiment of the invention, R² is an optionally substitutedC₁-C₆ alkyl or phenyl. In another embodiment, R² is —CF₃, —CH₃, or—C₆H₄CH₃. In another embodiment R² is —CF₃.

In another embodiment, the invention relates to a method of reactingcompound (4) with ketene dimethylacetal in the presence of catalyticmethanesulfonic acid to form tricycle compound (5A) in isopropyl acetate

In another embodiment the invention is drawn to a method of preparing amixture of mono acetylated compounds (6) and (7) by treating compound(5A) with water and 1 mole percent of methane sulfonic acid.

In another embodiment the invention is drawn to a method ofequilibrating a mixture of compounds (6) and (7) to cause an excess ofcompound (6) by heating above 70° C.

In another embodiment the invention is drawn to a method ofequilibrating a mixture of compounds (6) and (7) to cause an excessgreater than 90% of compound (6) over compound (7).

In another embodiment the invention is drawn to a method ofequilibrating a mixture of compounds (6) and (7) to favor compound (6)by heating above 70° C. in the presence of isopropyl acetate and water.

In another embodiment the invention is drawn to a method of oxidizing amixture of compounds (6) and (7) to form compound (8) and its hydratedform (9).

In another embodiment the invention is drawn to a method of oxidizing amixture of compounds (6) and (7) to form compound (8) and its hydratedform (9) by using sodium hypochlorite in the presence of TEMPO andsodium acetate biphasically with isopropyl acetate.

In another embodiment the invention is drawn to a method of reducingcompounds (8) or (9) or a mixture thereof to form compound (10) as asingle isomer.

In another embodiment the invention is drawn to a method of reducing amixture of compounds (8) and (9) to form compound (10) as a singleisomer using sodium triacetoxyborohydride.

In another embodiment the invention is drawn to a method of reducing amixture of compounds (8) and (9) to form compound (10) as a singleisomer using sodium triacetoxyborohydride in wet isopropyl acetate.

In another embodiment the invention is drawn to a method of isolatingcompound (8) from compound (9).

In another embodiment the invention is drawn to a method of reducingcompound (8) to form compound (10) as a single isomer.

In another embodiment the invention is drawn to a method of reducingcompound (8) to form compound (10) as a single isomer using a platinumon carbon catalyst in the presence of hydrogen.

In another embodiment the invention is drawn to a method of sulfonatingcompound (10) with a sulfonating agent in the presence of DMAP to form acompound of Formula (11).

In another embodiment the invention is drawn to a method of sulfonatingcompound (10) with a trifluoromethanesulfonic anhydride in the presenceof DMAP to form compound (11A) without the use of halogenated solventsor temperatures below 0° C.

In another embodiment the invention is drawn to a method of sulfonatingcompound (10) with trifluoromethanesulfonic anhydride in the presence ofDMAP to form compound (11A) in a mixture of isopropylacetate anddimethoxyethane at 5-10° C.

In another embodiment the invention relates to a method of displacingsulfonyl substituted compound (11A) with iodide at less than 60° C. inlower boiling organic solvents to form compound (12A)

In another embodiment the invention relates to a method of displacingsulfonyl substituted compound (11A) with sodium iodide in wet isopropylacetate and dimethoxyethane at 55° C. to form compound (12A).

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13).

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13) using catalytichydrogenation.

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13) using palladium hydroxideon carbon (Pearlman's Catalyst) in the presence of hydrogen.

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13) using hydrogen andcatalytic palladium hydroxide on carbon (Pearlman's Catalyst) in thepresence of an amine base such as diisopropylethylamine ortriethylamine.

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13) using hydrogen andcatalytic palladium hydroxide on carbon (Pearlman's Catalyst) in thepresence of diisopropylethylamine in ethanol and isopropyl acetate.

In another embodiment the invention is drawn to a method of reducingcompound (12A) to form hydrogen compound (13) using hydrogen andcatalytic palladium on carbon in the presence of triethylamine in ethylacetate.

In another embodiment the invention is drawn to a method of treatingcompound (13) with a catalytic amount of sulfuric acid and adding over12 hours acetic anhydride as an acylating agent in acetic acid to formcompound (2).

The method of the invention is particularly useful for the scalablecommercial production of the compounds described herein. The methods areoperationally simple, robust and efficient. In particular, the methodsare particularly useful for scaled-up production of deoxy sugars.Furthermore, the methods are cost-effective and demonstrate efficientthroughput and a significantly higher overall yield as compared to thepreparation methods used in the art.

DETAILED DESCRIPTION OF THE INVENTION

The term “comprising” (and its grammatical variations) as used herein isused in the inclusive sense of “having” or “including” and not in theexclusive sense of “consisting only of”. The terms “a” and “the” as usedherein are understood to encompass the plural as well as the singular.

As used herein, the term “halide” or “halo” refers to fluoride,chloride, bromide and iodide. The term halogen refers to fluorine,chlorine, bromine and iodine.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched, orcyclic moieties (including fused and bridged bicyclic and spirocyclicmoieties), or a combination of the foregoing moieties. For an alkylgroup to have cyclic moieties, the group must have at least three carbonatoms.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The “alkyl” and “aryl” groups are optionally substituted by 1-5substituents selected from —OH, halo, —CN, C₁-C₆ alkyl, arylalkyl, C₁-C₆alkoxy, C₁-C₆ alkenyl, C₁-C₆ hydroxyl, C₁-C₆ hydroxyalkyl, amino, C₁-C₆alkylamine, C₁-C₆ dialkylamine, wherein the alkyl groups can be furthersubstituted with one or more halogens.

The term “Ac” means acetyl.

The term “alkyl ketene acetal” means 1,1-dialkoxyethene.

The term “catalytic” means of involving or acting as a catalyst.

The term “stoichiometric” means an equivalent amount.

The compounds of the disclosure may exist as single stereoisomers,racemates and/or variable mixtures of enantiomers and/or diastereomers.All such single stereoisomers, racemates and/or variable mixtures ofenantiomers and/or diastereomers are intended to be within the scope ofthe present disclosure.

As used herein, the term “oxidizing agent” refers to a substance orspecies that gains electrons in a chemical reaction and the term“reducing agent” refers to a substance that loses electrons in achemical reaction.

The term “immunomodulator” refers to natural or synthetic productscapable of modifying the normal or aberrant immune system throughstimulation or suppression.

The terms “R” and “S” indicate the specific stereochemical configurationof a substituent at an asymmetric carbon atom in a chemical structure asdrawn.

The compounds of the invention may exhibit the phenomenon oftautomerism. While the formulae set forth herein cannot expressly depictall possible tautomeric forms, it is to be understood that the formulaeset forth herein are intended to represent any tautomeric form of thedepicted compound and is not to be limited merely to a specific compoundform depicted by the formula drawings.

As generally understood by those skilled in the art, an optically purecompound having one chiral center (i.e., one asymmetric carbon atom) isone that consists essentially of one of the two possible enantiomers(i.e., is enantiomerically pure), and an optically pure compound havingmore than one chiral center is one that is both diastereomerically pureand enantiomerically pure. Preferably, the compounds of the presentinvention are used in a form that is at least 90% free of otherenantiomers or diastereomers of the compounds, that is, a form thatcontains at least 90% of a single isomer (80% enantiomeric excess(“e.e.”) or diastereomeric excess (“d.e.”)), more preferably at least95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. ord.e.), and most preferably at least 99% (98% e.e. or d.e.).

Compound (2) is useful as an intermediate in the preparation of apharmaceuticals compounds such as5-amino-3-(2′-O-acetyl-3′-deoxy-β-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one(3) and pharmaceutically acceptable salts thereof. As described in U.S.application Ser. No. 11/873,202, the deoxyribofuranose compound (2) iscoupled with 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-one (1) to formcompound (3)

Compound (3) is used in methods for treating or preventing disease. Forinstance, compound (3) is used in methods of treating or preventing theonset and/or progression of tumors or cancers. Also disclosed aremethods of treating or preventing infection by a pathogen such as, forexample, viruses including Hepatitis B virus or Hepatitis C virus.Compound (3) is also used in methods of modulating immune cytokineactivity.

EXAMPLES

The following examples are for illustrative purposes only and are notintended to limit the scope of the claims.

In the synthetic schemes described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight.

Reagents were purchased from commercial suppliers such as AldrichChemical Company or Lancaster Synthesis Ltd. and were used withoutfurther purification unless otherwise indicated. All solvents werepurchased from commercial suppliers such as Aldrich, EMD Chemicals orFisher and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon at an ambient temperature (unlessotherwise stated) in anhydrous solvents, and the reaction flasks werefitted with rubber septa for the introduction of substrates and reagentsvia syringe or an addition funnel for liquids or a powder funnel forsolids.

The reactions were assayed by TLC and/or analyzed by LC-MS andterminated as judged by the consumption of starting material. Analyticalthin layer chromatography (TLC) was performed on glass-plates precoatedwith silica gel 60 F₂₅₄ 0.25 mm plates (EMD Chemicals), and visualizedwith UV light (254 nm) and/or iodine on silica gel and/or heating withTLC stains such as ethanolic phosphomolybdic acid, para-anisaldehydesolution with acid, ninhydrin solution, potassium permanganate solutionor ceric sulfate solution. Preparative thin layer chromatography(prepTLC) was performed on glass-plates precoated with silica gel 60F₂₅₄ 0.5 mm plates (20×20 cm, from Thomson Instrument Company) andvisualized with UV light (254 nm).

¹H-NMR spectra and ¹³C-NMR were recorded on a Varian Mercury-VX400instrument operating at 400 MHz. NMR spectra were obtained as CDCl₃solutions (reported in ppm), using chloroform as the reference standard(7.27 ppm for the proton and 77.00 ppm for carbon), CD₃OD (3.4 and 4.8ppm for the protons and 49.3 ppm for carbon), DMSO-d₆ (2.49 ppm forproton), or internally tetramethylsilane (0.00 ppm) when appropriate.Other NMR solvents were used as needed. When peak multiplicities arereported, the following abbreviations are used: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broadened), bs(broad singlet), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

Infrared (IR) spectra were recorded on an ATR FT-IR Spectrometer as neatoils or solids, and when given are reported in wave numbers (cm⁻¹). Massspectra reported are (+)-ES or APCI (+) LC/MS conducted by theAnalytical Chemistry Department of Anadys Pharmaceuticals, Inc.Elemental analyses were conducted by the Atlantic Microlab, Inc. inNorcross, Ga. Melting points (mp) were determined on an open capillaryapparatus, and are uncorrected.

The described synthetic pathways and experimental procedures may utilizemany common chemical abbreviations, DME (1,2-dimethoxy ethane), MTBE(methyl tert-butyl ether), TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl),2,2-DMP (2,2-dimethoxypropane), Ac (acetyl), ACN (acetonitrile), Bn(benzyl), BOC (tert-butoxycarbonyl), Bz (benzoyl), DBU(1,8-diazabicyclo[5,4,0]undec-7-ene), DCC(N,N′-dicyclohexylcarbodiimide), DCE (1,2-dichloroethane), DCM(dichloromethane), DEAD (diethylazodicarboxylate), DIEA(diisopropylethylamine), DMA (N,N-dimethylacetamide), DMAP(4-(N,N-dimethylamino)pyridine), DMF (N,N-dimethylformamide), DMSO(dimethyl sulfoxide), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride), Et (ethyl), EtOAc (ethyl acetate), EtOH (ethanol), HATU(O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate), HBTU(O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate),HF (hydrogen fluoride), HOBT (1-hydroxybenzotriazole hydrate), HPLC(high pressure liquid chromatography), IPA (isopropyl alcohol), KO^(t)Bu(potassium tert-butoxide), LDA (lithium diisopropylamide), MCPBA(3-chloroperoxybenzoic acid), Me (methyl), MeCN (acetonitrile), MeOH(methanol), NaH (sodium hydride), NaOAc (sodium acetate), NaOEt (sodiumethoxide), Phe (phenylalanine), PPTS (pyridinium p-toluenesulfonate), PS(polymer supported), Py (pyridine), pyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate),TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroaceticanhydride), THF (tetrahydrofuran), TLC (thin layer chromatography), Tol(toluoyl), Val (valine), and the like.

Example 1 Preparation of Compound (6) (Major) and Compound (7) (Minor)

(a) Step 1: Formation of Tricycle Compound (5A)

A 4 liter 4 necked flask equipped with a nitrogen inlet, additionfunnel, thermometer, and mechanical stirrer was charged withmonoacetonexylose (152.16 grams, 800 mmol) and isopropylacetate (1200ml) and stirred until the solids dissolved, yielding a slightly cloudysolution. Ketenedimethylacetal (3.36 ml, 35.5 mmol) was added and thereaction cooled to 3° C. using an ice bath. Methanesulfonic acid (0.52ml, 8 mmol) was added followed by the dropwise addition ofketenedimethylacetal (80 ml, 844.5 mmol) over 45 minutes. The reactiontemperature reached 10° C. during the addition. When the addition wascomplete TLC, using 80% MTBE in hexane, indicated a complete, cleanconversion to the much faster running tricycle 5A. The ice bath wasremoved.

(b) Step 2: Hydrolysis of Compound 5A to a Mixture of Monoacetates

Water (72 ml, 4000 mmol) was added all at once to the above reaction andthe mixture stirred at ambient temperature for 90 minutes. The TLC ofthe reaction using 80% MTBE in hexane indicated two new mid-polarityproducts were formed with the slower running of the two being the majorproduct.

The reaction was transferred to a 2 liter separatory funnel and shakenwith a 120 ml of an aqueous solution (60 ml 1.0M NaHCO₃, 60 ml 30%NaCl), the phases split and the organic phase was transferred to a roundbottom flask and the volatiles were removed in vacuo.

(c) Step 3: Equilibration to Compound (6).

The material isolated from the evaporation was reconstituted in freshisopropylacetate (1200 ml) and water (72 ml) and heated to 77° C. for 12hours, then cooled to ambient temperature. A TLC analysis using 80% MTBEin hexane indicated that the faster running of the two products is themajor product with only a trace of the slower running isomer present.

A 0.2 ml sample of the reaction mixture was evaporated to dryness toyield 37 mg of a solid. ¹H NMR confirms that the desired acetatecompound (6) is the very major product. ¹H NMR (400 MHz, CDCl₃) δ: 5.92(1H, d, J=3.3 Hz), 4.51-4.56 (2H, m), 4.24-4.28 (1H, m), 4.13-4.19 (2H,m), 2.98 (1H, d, J=4.0 Hz), 2.11 (3H, s), 1.51 (3H, s), 1.33 (3H, s).

Example 2 Preparation of Compounds (8) and (9)

The 4 liter flask that already contains approximately 0.8 Moles ofcompound (6) in wet isopropylacetate from the previous step was equippedwith a nitrogen inlet, thermometer, addition funnel and a mechanicalstirrer. TEMPO (800 mg) was added and the mixture was stirred and cooledin an ice bath. In a separate flask an aqueous solution containing 64.3grams of sodium bromide, 98.4 grams of sodium acetate dissolved in 320ml of deionized water was cooled to 5° C. When the reaction temperaturereached 5° C. the pre-cooled aqueous solution was added to it to form abiphasic reaction mixture. To this cold solution was added dropwise 735ml of aqueous sodium hypochlorite solution (titrated directly beforeuse, 10.15% or 1.36M, 1.002 Moles, 1.25 equivalents) over 2 hours,keeping the exothermic addition at or below 7° C. When the addition wascomplete stirring was continued for 30 minutes and the TLC (80%MTBE-hexane) indicated a complete conversion to the slower runningketone.

The reaction was transferred to a 4 liter separatory funnel and thephases split. The dark organic portion was washed once with 160 ml ofaqueous 2.5% sodium thiosulfate solution. The resulting pale yelloworganic portion was washed with 160 ml of 30% sodium chloride solution.The aqueous phases were combined and 44.1 grams of solid sodium chloridewas added and stirred until all of the salt dissolved. The resultingaqueous solution was extracted twice with 400 ml portions ofisopropylacetate, the organic extracts were combined, and washed oncewith 50 ml of 30% sodium chloride solution. All of the organic portionswere combined to give a slightly cloudy solution.

A 0.25 ml portion of this solution was evaporated to give 14 mg of asolid. ¹H NMR confirms the presence of both the ketone and the hydrateas an approximately 1:1 mixture. ¹H NMR (400 MHz, CDCl₃) δ: 6.09 (1H, d,J=4.4 Hz, Compound 8), 5.84 (1H, d, J=3.9 Hz, Compound 9), 4.61 (1H, dd,J₁=11.7 Hz, J₂=6.3 Hz, Compound 9), 4.56 (1H, t, J=3.3 Hz, Compound 8),4.36-4.42 (2H, m, Compounds 8 and 9), 4.20-4.24 (2H, m, Compounds 8 and9), 4.06-4.15 (2H, m, Compounds 8 and 9), 2.11 (3H, s, Compound 9), 2.05(3H, s, Compound 8), 1.58 (3H, s, Compound 9), 1.50 (3H, s, Compound 8),1.43 (3H, s, Compound 8), 1.36 (3H, s, Compound 9).

Example 3 Preparation of Compound (10)

A 4 liter 4-necked flask equipped with a nitrogen inlet, powder funnel,thermometer, and mechanical stirrer was charged with the cloudy organicsolution of ketone (8) and its hydrate (9). This was cooled whilestirring to 4° C. using an ice bath. To this cold solution was addedfour 42.4 gram portions of solid sodium triacetoxyborohydride in 15minute intervals. After the final addition the reaction was stirred at5° C. for 60 minutes.

While stirring at 5° C. 1.0 M aqueous sodium carbonate solution (800 ml)was added quickly. The reaction temperature rises to 12° C. and a smallamount of gas evolution occurs. The mixture thickens substantially.After stirring 15 minutes the reaction is transferred to a 4 literseparatory funnel and the phases split, the aqueous portion containssome solid. The organic portion was stirred with 2.0 M aqueous sodiumcarbonate solution (400 ml) for 10 minutes, the phases split and bothaqueous phases were combined. The solid in the aqueous phase wasfiltered and then was dissolved in water (600 ml) and added back to theresulting homogeneous aqueous phase. The aqueous phase was extractedwith two 200 ml portions of isopropylacetate and the organic portionswere combined. The total weight of the organic phase was 2,370.5 grams.

A 5 gram portion of the organic phase was evaporated to give 243 mg ofoil that crystallized under vacuum. Calculated yield: 2370.5 gramssolution×0.243 grams product/5 grams solution=115.2 grams (496.15 mmol,62%) of compound 10. ¹H NMR indicates this is a very pure sample. ¹H NMR(400 MHz, CDCl₃) δ: 5.82 (1H, d, J=3.9 Hz), 4.58 (1H, t, J=4.3 Hz), 4.43(1H, dd, J₁=12.4 Hz, J₂=2.4 Hz), 4.16-4.20 (1H, m), 3.93-3.97 (1H, m),3.81-3.87 (1H, m), 2.45 (1H, d, J=10.8 Hz), 2.10 (3H, s), 1.58 (3H, s),1.38 (3H, s).

A 4 liter 4-necked flask equipped with a short path distillation head, atemperature probe and mechanical stirring was charged with the 2,370.5gram organic phase. This was heated to remove 2400 ml of distillate atatmospheric pressure. Fresh isopropylacetate (1500 ml) was added to theflask and 1500 ml were removed by distillation. The reaction flask wasthen diluted with 920 ml of isopropylacetate to give a slightly cloudysolution. This solution is now ready to be taken to the next step.

Example 4 Alternative Preparation of Compounds (8) and (10)

(a) Step 1: Preparation of Compound (8)

The flask that contained Compound 6 (approximately 0.2 mol in wetisopropyl acetate from Example 1 was equipped with a nitrogen inlet,thermometer, addition funnel and a magnetic stirrer. TEMPO (200 mg) wasadded and the mixture was stirred and cooled in a 0° C. ice bath. In aseparate flask an aqueous solution containing sodium bromide (16.08 g)and sodium acetate (24.6 g) dissolved deionized water (80 mL) was cooledto 5° C. When the reaction temperature reached 5° C. the pre-cooledaqueous solution was added to it to form a biphasic reaction mixture.

To this cold mixture was added dropwise an aqueous sodium hypochloritesolution (labeled 10-15%; 180 mL) over 1 h, keeping the exothermicaddition at or below 7° C. When the addition was complete TLC (80%MTBE-hexanes) indicated a complete conversion to the lower R_(f) ketone.The cooling bath was removed and solid NaCl (25 g) was added. Afterstirring for 30 min., the mixture was transferred to a 1-L separatoryfunnel and the phases were then separated. The dark organic portion wasshaken with 1.0 M NaHCO₃ (25 mL), and then 2.0 M Na₂SO₃ (30 mL) wasadded and shaking was continued until all of the color dissipated (someout-gassing occurred).

The resulting clear organic portion was washed once with 15% aqueousNaCl (20 mL). The clear organic phase was transferred to a 1-L flaskequipped with a temperature probe, a distillation head, and magneticstirring. The temperature was set to 85° C. to distill the solvent. Whenthe distillation stopped, the temperature was raised to 105° C. tocomplete the distillation. The distillation flask was cooled to ambienttemperature and the mixture was diluted with isopropylacetate (100 mL).Activated carbon (Darco G60; 5 g) was added and the mixture was stirredat ambient temperature for 90 min. This mixture was filtered usingCelite and the solids were washed with isopropyl acetate (2×30 mL). Thepale yellow filtrate weighed 220.5 g. 2.0 mL of this solution(weight=1.826 g) was evaporated to yield 0.189 g of a pale yellow oil.Calculation showed a solution concentration of 0.41 M of Compound 8 andtotal yield of 22.86 g (49.6% from monoacetone xylose). ¹H NMR (400 MHz,CDCl₃) δ: 1.43 (3H, s), 1.50 (3H, s), 2.05 (3H, s), 4.21 (1H, dd,J₁=11.9 Hz, J₂=3.9 Hz), 4.37 (1H, d, J=4.7 Hz), 4.40 (1H, dd, J₁=12.5Hz, J₂=3.2 Hz), 4.56 (1H, t, J=3.1 Hz), 6.09 (1H, d, J=3.8 Hz). ¹H-NMRshowed that only Compound 8 was present (Compound 9 was absent).

b. Step 2: Preparation of Compound (10)

A 250-mL three-necked round bottom flask equipped with a temperatureprobe, a balloon filled with hydrogen gas, and magnetic stirring, wascharged 62 mL of the 0.41 M solution of compound 8 prepared above andwet 3% Pt-C (2.05 g, Johnson Matthey type B101018-3, lot C-9264, 58.25%water). The temperature was equilibrated to 26° C., the mixture degassedwith house vacuum and flushed with hydrogen gas three times, and themixture was then stirred vigorously under a hydrogen atmosphere for 16h. GC analysis indicated a complete conversion to Compound 10. Thesolution was filtered through Celite filter aid, the solids were washedwith isopropyl acetate (2×30 mL), and the clear, colorless filtrate wasthen evaporated to give 5.74 g of oil that crystallized. ¹H-NMRconfirmed Compound (10) as the only product.

Example 5 Preparation of Compound (11A)

The 4 liter flask that already contains approximately 496.15 mmol ofcompound 10 in dry isopropylacetate from Example 3 was equipped with anitrogen inlet, thermometer, rubber septum and a mechanical stirrer. Ina separate flask DMAP (90.92 grams, 744.23 mmol, 1.5 eq) was dissolvedin 255 ml of hot DME. The hot solution was added to the reaction flaskand the reaction was cooled in an ice bath to 5° C.Trifluoromethanesulfonic anhydride (104.34 ml, 620.19 mmol, 1.25 eq) wasadded at 1.17 ml/minute using a syringe pump. The maximum temperaturereached during the addition was 7° C. When the addition was complete andthe reaction temperature returned to 5° C. a TLC (20% EtOAc-Toluene)indicated a complete, clean conversion to the faster running triflate.

To the 5° C. reaction was added 1.0M HCl (745 ml) causing a 9° C.exotherm. After stirring 5 minutes the reaction was transferred toseparatory funnel and the phases split. The organic phase was washedwith two portions of 1.0 M HCl (300 ml) and once with 240 ml of anaqueous solution (120 ml 1.0 M NaHCO₃, 120 ml 30% sodium chloride). Allof the aqueous phases were combined and extracted once with 500 ml ofisopropylacetate. The extract was washed with two 100 ml portions of 1.0M HCl and once with 80 ml of aqueous solution (40 ml 1.0 M NaHCO₃, 40 ml30% sodium chloride). All of the organic phases were combined to get aslightly cloudy solution of the triflate 11A.

A 0.25 ml portion of this solution was evaporated to get 22 mg of anoil. ¹H NMR indicates this is a very pure sample of the triflate alongwith a small amount of residual isopropylacetate. ¹H NMR (400 MHz,CDCl₃) δ: 5.85 (1H, d, J=3.9 Hz), 4.85 (1H, dd, J₁=8.6 Hz, J₂=4.6 Hz),4.77 (1H, t, J=4.3 Hz), 4.37-4.42 (2H, m), 4.22-4.26 (1H, m), 2.11 (3H,s), 1.61 (3H, s), 1.40 (3H, s).

Example 6 Preparation of Compound (12A)

A 4 liter 4 necked flask equipped with a nitrogen inlet, temperatureprobe, condenser and mechanical stirrer was charged with theisopropylacetate solution of the triflate (assumed to be 496.15 mmol)and 255 ml of DME. Solid sodium iodide (111.55 grams, 744.23 mmol, 1.5eq) was added and the mixture stirred at 55° C. for 17 hours. A TLC (10%EtOAc-Toluene) indicates a complete conversion to iodide.

Water (400 ml) was added and the mixture stirred rapidly for fiveminutes. The mixture was transferred to a separatory funnel and thephases split. The organic phase was washed once with 400 ml of anaqueous solution (200 ml of 1.0M NaHCO₃ and 200 ml of 30% NaCl). Theaqueous phases were combined and extracted once with theisopropylacetate (400 ml). The extract was washed once with water (100ml) and once with 100 ml of aqueous solution (50 ml of 1.0M NaHCO₃ and50 ml of 30% NaCl). All of the organic phases were combined.

The solution of compound 12A was transferred to a 3 liter round bottomflask equipped with a short path distillation head. Two liters ofsolvent were removed by simple distillation. The mixture was cooled toambient temperature and the residual volume was determined to be 500 ml.To this was added 183 ml of isopropylacetate and 208 ml of 200 proofethanol to generate a 0.5M solution of compound 12A in a 20%ethanol/isopropylacetate solution.

A 0.2 ml aliquot was removed and evaporated to get 42 mg of an oil. ¹HNMR indicates this is a very pure sample of compound 12A. ¹H NMR (400MHz, CDCl₃) δ: 6.02 (1H, d, J=2.9 Hz), 5.04 (1H, d, J=2.9 Hz), 4.35 (1H,d, J=3.1 Hz), 4.15-4.24 (2H, m), 3.77-3.80 (1H, m), 2.10 (3H, s), 1.52(3H, s), 1.33 (3H, s).

Example 7 Preparation of Compound (13)

A 3 liter round bottom flask equipped with a large magnetic stir bar wascharged with the solution of compound 12A (assumed 496.15 mmol as a 0.5M solution in 20% ethanol/isopropylacetate), Diisopropylethylamine(112.34 ml, 644.8 mmol, 1.3 eq) and 20.37 grams of 20% Pd(OH)₂/C(Pearlman's Catalyst). While stirring rapidly the reaction was degassedwith a light vacuum and then filled with hydrogen gas three times. Thereaction was then stirred under an atmosphere of hydrogen for 18 hours.A TLC (10% EtOAc-toluene) indicated a clean, complete conversion to theslower running hydrogen compound.

The reaction was filtered through Celite and the dark solids washed withtwo 200 ml portions of isopropylacetate. The filtrate was transferred toa 4 liter separatory funnel and washed once with 1.0 M HCl (645 ml),once with 200 ml of an aqueous solution (100 ml 2.5% sodium thiosulfate,100 ml 1.0M NaHCO₃) and once with 200 ml of 30% NaCl. All of the aqueousphases were combined and extracted with two 200 ml portions ofisopropylacetate. The extracts were combined and washed once with 80 mlof an aqueous solution (40 ml 2.5% sodium thiosulfate, 40 ml 1.0MNaHCO₃) and once with 80 ml of 30% NaCl. The organic portions werecombined, transferred to a 3 liter round bottom flask and 1.5 liters ofsolvent was removed by atmospheric distillation. The cooled residue hada volume of 450 ml. 50 ml of isopropylacetate was added to form asolution close to 1.0 M and 10 grams of Norit charcoal was added and themixture stirred two hours at ambient temperature.

This was then filtered through Celite to give a clear, golden coloredfiltrate. The filtrate was concentrated in vacuo to give 103.47 grams(478.52 mmol) of a golden colored clear oil. ¹H NMR indicates a veryhigh purity of compound 13. ¹H NMR (400 MHz, CDCl₃) δ: 5.83 (1H, d,J=3.7 Hz), 4.74 (1H, t, J=4.2 Hz), 4.39-4.45 (1H, m), 4.28 (1H, dd,J₁=11.8 Hz, J₂=3.1 Hz), 4.08 (1H, dd, J₁=12.5 Hz, J₂=6.2 Hz), 2.07-2.12(4H, m), 1.62-1.69 (1H, m), 1.52 (3H, s), 1.33 (3H, s).

Compound 13 can be further purified by vacuum distillation if required.BP=70° C. at 0.025 mm Hg.

Example 8 Preparation of Compound (2)

A 25 ml round bottom flask equipped with magnetic stirring and a rubberseptum was charged with compound 13 (640 mg, 2.96 mmol) and 5 ml ofacetic acid. In a separate flask acetic anhydride (0.562 ml, 6 mmol, 2eq) was diluted to a total volume of 2.0 ml with acetic acid and 0.1 mlof this acetic anhydride solution was added to the reaction mixture.Sulfuric acid (0.15 ml of a 1.0M solution in acetic acid, 0.15 mmol,0.05 eq) was added to the reaction, and then the balance of the aceticanhydride solution (1.9 ml) was added over 12 hours using a syringepump. A TLC (30% EtOAc-hexane) shows a very clean conversion to thedesired compound 2.

The reaction was diluted with toluene and evaporated in vacuo. Theresidue was dissolved in MTBE, stirred with 10% sodium carbonate for 15minutes and the phases split. The organic portion was dried (MgSO₄),filtered through a small pad of silica gel and evaporated to get 680 mg(2.61 mmol) of a clear oil. ¹H NMR shows this to be a clean mixture ofboth anomers.

It is important to note that the construction and arrangement of themethods and steps shown in the exemplary embodiments is illustrativeonly. Although only a few embodiments of the present disclosure havebeen described in detail, those skilled in the art will readilyappreciate that many modifications are possible without materiallydeparting from the novel teachings and advantages of the subject matterrecited in the claims. Accordingly, all such modifications are intendedto be included within the scope of the present disclosure as defined inthe appended claims. The order or sequence of any method or method stepsmay be varied or re-sequenced according to alternative embodiments.Other substitution, modification, changes and omissions may be made inthe design, operating conditions and arrangement of the embodimentswithout departing from the spirit of the present disclosure as expressedin the appended claims.

I claim:
 1. The compound